Principles and Applications of Asymmetric Synthesis

352 ASYMMETRIC CATALYTIC HYDROGENATION AND OTHER REDUCTION REACTIONS

6.1.2.7 Examples of Potential Industrial Applications. Ru±BINAP dicarboxylate complexes catalyze the hydrogenation of a variety of functionalized prochiral ole®ns with high enantioselectivity. The pure diacetate complex can be prepared in good yield11 by treating [RuCl2(COD)]n ®rst with (R)- or (S)- BINAP and triethylamine in toluene at 110 C, followed by sodium acetate treatment in t-butyl alcohol at 80 C or, more conveniently, by treatment of RuCl2(benzene)2 with BINAP in DMF at 100 C and then with excess sodium acetate.45

Takaya and co-workers46 found that BINAP-based Ru(II) dicarboxylate complexes 31 can serve as e½cient catalyst precursors for enantioselective hydrogenation of geraniol (2E )-32 and nerol (2Z)-32. (R)- or (S)-citronellal 33 is obtained in nearly quantitative yield with 96±99% ee. The nonallylic double bonds in geraniol and nerol were intact. Neither double bond migration nor (E )-/(Z)-isomerization occurred during the catalytic process. Furthermore, the S/C ratio was extremely high, and the catalyst could easily be recovered (Scheme 6±18). This process can be applied to the asymmetric synthesis of a key intermediate for vitamin E.

Scheme 6±18

6.1 INTRODUCTION 353

The catalytic hydrogenation of enamide 34 in the presence of 0.5±1 mol% of (R)-BINAP complex in a 5:1 mixture of ethanol and dichloromethane under 1± 4 atm of hydrogen a¨ords 35 with quantitative yield and higher than 99.5% ee. The (E )-isomer is not reduced under similar reduction conditions. This approach provides a route to a number of alkaloid compounds (Scheme 6±19).47

Scheme 6±19

Naproxen is a nonsteroidal antiin¯ammatory drug, and its (S)-form is about 30 times more active than its (R)-form. The Ru±BINAP-catalyzed asymmetric hydrogenation of substrate 36 o¨ers an entry to an enantiomerically pure (S)-form of the drug 37 (Scheme 6±20).11a

Scheme 6±20

Because naproxen is an extremely attractive target product for catalytic asymmetric synthesis due to its large volume and high value, the development of this chemistry is expected to be of high commercial interest. Extensive e¨ort in repeating this experiment by Chan et al.11b±d showed that, under the above conditions, generally 93±94% ee could be obtained. The small di¨erence in ee might be due to analytical discrepancy. The ee values increased somewhat when the reaction was carried out at lower temperature. It should be pointed out that, while there are many good catalysts for the asymmetric hydrogenation of enamides, only Ru±BINAP-type catalysts are e¨ective for the hydrogenation of 2-arylacrylic acids (with ee >90%). Further development of the Noyori chemistry is clearly of high scienti®c and practical interest. To expand the scope of the BINAP (or chiral biaryl) chemistry to include pyridyl species, Chan et al. developed a new class of chiral pyridylphosphine ligand, 2,20,6,60-tetramethoxy- 4,40-bis(diphenylphosphino)-3,30-bipyridine (P-Phos, 38a).48a

354 ASYMMETRIC CATALYTIC HYDROGENATION AND OTHER REDUCTION REACTIONS

The Ru(P-Phos) catalyst was found to be highly enantioselective in asymmetric hydrogenation of 36 leading to 37. The best ee obtained at 0 C under 1000 psig H2 was 96.2%. (A side-by-side comparison study using Ru±BINAP catalyst gave 94.8% ee.) The asymmetric hydrogenation of b-keto esters using Ru(P-Phos) catalyst also gave up to 99% ee. Other chiral biaryl ligands with heterocyclic moieties may also be considered as o¨shoots of the BINAP family. Bennincori et al.48b synthesized (‡)- and (ÿ)-2,20-bis(diphenylphosphino)- 4,40,6,60-tetramethyl-3,30-bis(benzothiophene) 38b and found its Ru complex catalyzed the asymmetric hydrogenation of b-keto esters to give b-hydroxy esters in up to >99% ee. Another ligand, 2,20-bis(diphenylphosphino)-1,10-bis- (dibenzofuranyl) 38c, was developed by Bayer for the asymmetric hydrogenation leading to (S)-ketoprofen (Scheme 6±21).48c It is expected that Noyori's innovative concept is a good foundation based on which more e¨ective new catalysts can be developed.

Scheme 6±21

Isomerization of allylic amines is another example of the application of the BINAP complex. Rh±BINAP complex catalyzes the isomerization of N,N- diethylnerylamine 40 generated from myrcene 39 with 76±96% optical yield. Compound (R)-citronellal [(R)-42], prepared through hydrolysis of (R)-41, is then cyclized by zinc bromide treatment.49 Catalytic hydrogenation then completes the synthesis of (ÿ)-menthol. This enantioselective catalysis allows the annual production of about 1500 tons of menthol and other terpenic substances by Takasago International Corporation.50

(S)-citronellal 42 can also be prepared similarly from 40. Asymmetric hydrogenation of (R)-43 provides 44, which can be used to make the side chain of vitamins E and K (Scheme 6±22).

6.2 ASYMMETRIC REDUCTION OF CARBONYL COMPOUNDS

355

Scheme 6±22

6.2ASYMMETRIC REDUCTION OF CARBONYL COMPOUNDS

Asymmetric reduction of carbonyl compounds can usually be achieved either through direct catalytic hydrogenation or by metal hydride reduction. It should be mentioned here that reduction of carbonyl compounds by catalytic hydrogenation may not be chemoselective. Other co-existing functional groups such as the CbC bond may also undergo hydrogenation.

LiAlH4 is a very powerful reducing agent and hence does not show much chemoselectivity compared with other metal hydrides. Replacing some of the hydrogen atoms in LiAlH4 with alkoxyl groups makes it less reactive and more selective. Similarly, to achieve the stereoselective delivery of hydride to one prochiral face of prochiral ketones, LiAlH4, NaBH4, and borane-tetrahydrofuran (BH3 THF) have been modi®ed with chiral ligands. This line of work has been extensively reviewed. Interested readers may refer to Midland51a and Srebnik.51b

356 ASYMMETRIC CATALYTIC HYDROGENATION AND OTHER REDUCTION REACTIONS

6.2.1Reduction by BINAL±H

One approach to enantioselective reduction of prochiral carbonyl compounds is to utilize chiral ligand-modi®ed metal hydride reagents. In these reagents, the number of reactive hydride species is minimized in order to get high chemoselectivity. Enantiofacial di¨erentiation is due to the introduced chiral ligand.

The ®rst e¨ort to modify LiAlH4 with a chiral ligand was reported in 1951,52 but signi®cant results had not been achieved until 1979 when Noyori53 developed a binaphthol-modi®ed aluminum hydride reagent (abbreviated to BINAL±H) of type 45. The compound can be generated in situ by mixing LiAlH4 with equimolar amounts of optically pure (S)-(ÿ)-/(R)-(‡)-binaphthol and another hydroxylic component R00OH. As would be expected from the excellent stereoselectivity of other reactions induced by BINAP complexes or catalysts derived from binaphthol, compound 45 also gives excellent results in reducing ketones. Binaphthoxy group binding in a bidentate fashion in a metal complex can provide excellent di¨erentiation between the prochiral faces of a substrate. A reagent with a simple alkoxyl group in 45, such as CH3O or C2H5O, exhibits high enantioselectivity, and the optical yields can be further enhanced by lowering the reaction temperature to ÿ78 C or lower.

In general, (R)-45 reduction gives (R)-carbinol preferentially, and (S)-45 provides the (S)-enantiomer predominantly (Scheme 6±23). This can be explained by the reaction transition state shown in Figure 6±4. The oxygen atom of the R00O group, which has the highest basicity, acts as the binding atom in the quasi-aromatic, six-membered ring transition state.

The two chair-like transition states 48 and 49 have been suggested to explain the stereochemistry in the reaction. Here structure 48, leading to (S)-carbinol, is favored over the diastereomeric 49, which gives the (R)-enantiomer, because the latter structure with axial-R0 and equatorial-R group is destablized by the n-p

Scheme 6±23. R0 is an unsaturated group.

6.2 ASYMMETRIC REDUCTION OF CARBONYL COMPOUNDS

357

Figure 6±4. Transition state of BINAL±H reduction.

electron repulsion between the axially orientated binaphthoxy oxygen and the unsaturated moiety. It should be noted that the overwhelming kinetic preference is primarily determined by the di¨erence in electronic properties of the R0 and R attached to the carbonyl group. Steric factors are also of some signi®- cance, but do not overbalance the electronic one.

Reduction of aromatic ketones by 45 normally gives satisfactory results. Scheme 6±24 and Table 6±4 show the results of some such reactions.

Similarly, high stereoselectivity has also been observed in acetylenic ketone or ole®nic ketone reductions (Scheme 6±25).

Scheme 6±24

TABLE 6±4. Enantioselective Reduction of Aromatic Ketones with BINAL±H (R00O±±C2H5O)

		Carbinol Product
Ketone	Con®g. of BINAL±H	Yield (%)	ee (%)	Con®g.
C6H5COCH3	R	61	95	R
C6H5COC2H5	S	62	98	S
C6H5CO-n-C3H7	S	78	100	S
C6H5CO-n-C4H9	S	64	100	S
C6H5COCH(CH3)2	S	68	71	S
C6H5COC(CH3)3	R	80	44	R
a-Tetralone	R	91	62	R

ee ˆ Enantiomeric excess.

358 ASYMMETRIC CATALYTIC HYDROGENATION AND OTHER REDUCTION REACTIONS

Scheme 6±25

The optically active propargylic and allylic alcohols thus obtained are important synthetic intermediates in the enantioselective synthesis of insect pheromones, prostaglandins, prostacyclins, and many other bioactive compounds (Scheme 6±26).53

Scheme 6±26. Some important compounds prepared via BINAL±H reduction.

BINAL±H reagents 45 are not e¨ective in the enantioselective reduction of dialkyl ketones.53 For example, reaction of benzyl methyl ketone with (S)-45 gives (S)-1-phenyl-2-propanol in only 13% ee (71% yield). Reaction of 2- octanone with (R)-45 produces (S)-2-octanol in 24% ee (67% yield).53 This drop of ee values in the reaction may be explained by the lower energy di¨erence between the favored transition state 48 and unfavored transition state 49 caused by the lack of the above-mentioned n-p repulsion between the reductant and the substrate dialkyl ketone.

If we compare the above result with the following example, we can easily see

6.2 ASYMMETRIC REDUCTION OF CARBONYL COMPOUNDS

359

how important this n-p repulsion is for getting high enantioselectivity. In the reduction of 1-deuterium aldehydes, good results can still be obtained, even though there is only a small steric di¨erence between H and D. The enantioselectivity, of course, is not as high as that for acetylenic or ole®nic ketones, but it is still far higher than that for dialkyl ketone reactions (see Scheme 6±27). All these results support the postulated mechanism in Figure 6±4 where transition state 48 is favored over 49.

Scheme 6±27. Asymmetric reduction of 1-deutero aldehyde.

TABLE 6±5. Enantioselective Reduction of Deterium-Labeled Aldehydes with BINAL±H (R00O±±C2H5O)

		Carbinol Product
Aldehydes	Con®g. of BINAL±H	Yield (%)	ee (%)	Con®g.
Geranial-1-d	S	91	91 or 84	S
Neral-1-d	S	90	72	S
(E,E)-Farnesal-1-d	R	91	88	R
(Z,E)-Farnesal-1-d	R	93	82	R
Benzaldehyde-a-d	R	75	82	R

ee ˆ Enantiomeric excess.

6.2.2 Transition Metal±Complex Catalyzed Hydrogenation of

Carbonyl Compounds

Asymmetric hydrogenation of ketones is one of the most e½cient methods for making chiral alcohols. Ru±BINAP catalysts are highly e¨ective in the asymmetric hydrogenation of functionalized ketones,54,55 and this may be used in the industrial production of synthetic intermediates for some important antibiotics. The preparation of statine 65 (from 63b: R ˆ i-Bu) and its analog is one example (Scheme 6±28).56 Table 6±6 shows the results when asymmetric hydrogenation of 63 catalyzed by RuBr2[(R)-BINAP] yields threo-64 as the major product.

Chiral diols are highly useful ligands for preparing chiral reagents, catalysts, and other chiral ligands. For example, enantiomerically pure 1,2-, 1,3-, and 1,4- diols are important intermediates for preparing useful chiral diphosphine ligands such as Chiraphos,57 Skewphos,58 and DuPhos.59 These diols can be prepared through asymmetric reduction of the corresponding diones via hydrogenation,55,60 borane reduction,61 hydrosilylation,62 or enzymatic reduction.63

360 ASYMMETRIC CATALYTIC HYDROGENATION AND OTHER REDUCTION REACTIONS

Scheme 6±28. Statine 65, part of aspartic proteinase inhibitor.

TABLE 6±6. Asymmetric Hydrogenation of 64

		Product 64		threo-64
Substrate	Catalyst	Yield (%)	threo:erythro	ee (%)
63a	RuBr2[(R)-BINAP]	97	>99:1	99
63a	RuBr2[(S)-BINAP]	96	9:91	>99
63b	RuBr2[(R)-BINAP]	99	>99:1	97
63c	RuBr2[(R)-BINAP]	92	>99:1	100

From a practical point of view, the catalytic asymmetric hydrogenation of the corresponding diones will be the preferred method if high yields and high enantioselectivity can be ensured. Recently, over 98% yield with more than 99% ee has been achieved by optimizing the reaction conditions.64 For example, asymmetric hydrogenation of 2,4-pentanedione catalyzed by Ru±BINAP complex in the presence of hydrochloric acid gave 2,4-pentanediol in more than 95% yield and over 99% ee (Scheme 6±29).64

Scheme 6±29

The Ru±BINAP diacetate complex, which gives good results in the enantioselective hydrogenation of various ketones, is ine¨ective in the hydrogenation of methyl 3-oxobutanoate. Reactivity in methanol is low, and the enantioselectivity is discouragingly poor. As the carboxylate ligands in Ru complexes may also be replaced by other anions, it is possible to introduce a strong acid anion by

	6.2 ASYMMETRIC REDUCTION OF CARBONYL COMPOUNDS				361
TABLE 6±7. Ru±BINAP±Catalyzed Enantioselective Hydrogenation Reactions of
Methyl 3-Oxobutanoate
Catalyst System		S/C	Time (h)	Yield (%)	ee (%)
Ru(OCOCH3)2(BINAP)		1400	60	1	Ð
Ru(OCOCH3)2(BINAP) ‡ 2CF3COOH		1620	32	99	15
Ru(OCOCH3)2	(BINAP) ‡ 2HClO4	1620	32	99	51
Ru(OCOCH3)2	(BINAP) ‡ 2HCl	1800	32	99	51
Ru(OCOCH3)2	(BINAP) ‡ 2HCl	10,000	64*	98	96
RuCl2(BINAP)		2000	36	99	99
RuBr2(BINAP)		2100	43	99	99
RuI2(BINAP)		1400	40	99	99

* Reaction carried out at 100 C. ee ˆ Enantiomeric excess.

adding strong acids under acid±base thermodynamic equilibration.65 Indeed, the addition of 2 equivalents of tri¯uoroacetic acid or aqueous perchloric acid to remove the acetate ligands greatly increases the catalytic activity, but the enantioselectivity remains moderate. Addition of hydrochloric acid results in a remarkable enhancement of catalytic e½ciency.55,66

Scheme 6±30 shows that the halogen-containing complexes RuX2(BINAP) are excellent catalysts: With an S/C of over 103 or even 104, the enantioselective hydrogenation of methyl 3-oxobutanoate can still proceed well in methanol. The yield of the enantioselective reaction is almost 100%.

Scheme 6±30

In the case of hydrogenation using [Ru(BINAP)Cl2]n as the catalyst precursor, the reaction seems to occur by a monohydride mechanism as shown in Scheme 6±31. On exposure to hydrogen, RuCl2 loses chloride to form RuHCl species A, which in turn reversibly forms the keto ester complex B. Hydride transfer occurs in B from the Ru center to the coordinated ketone to form C. The reaction of D with hydrogen completes the catalytic cycle.67

This asymmetric catalytic reaction has found wide application in converting functionalized ketones to the corresponding secondary alcohols with high ee. A general illustration is given in Scheme 6±32. Fiveto seven-membered chelate complexes, formed by the interaction of the Ru atom with carbonyl oxygen and a heteroatom X, Y, or Z may be the key intermediates that cause the high enantioselectivity in the reaction.67